Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Membrane Channels in Physiology and Pathology

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 28315

Share This Special Issue

Special Issue Editors

Prof. Dr. Antonio Ferrer-Montiel

E-Mail Website
Guest Editor

IDiBE, Universitas Miguel Hernández, Edificio Torregaitán, 03202 Elche, Spain
Interests: sensory neurobiology; pathophysiology of pain; TRP channels; pain pharmacology; drug discovery
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Antonio Felipe

E-Mail Website
Guest Editor

Department of Biochemistry and Molecular Medicine, Institut de Biomedicina, Universitat de Barcelona, Avda. Diagonal 643, 08028 Barcelona, Spain
Interests: voltage-dependent potassium channels; functional complex; oligomeric association; traffic; lipid rafts; post-translational modifications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ion channels are integral membrane proteins that play essential physiological roles. These specialized membrane proteins are responsible for the ions fluxes across the plasma membrane of all mammalian cells. Channels form functional oligomeric complexes by association with ancillary proteins, contributing to the cellular homeostasis and maintenance of health. Numerous cellular events control and are controlled by channel gating and kinetics. Membrane channels, with different ion selectivity, regulate membrane potential and excitability, shape the action potential, and elicit muscle contraction, among other cellular processes. Due to their contribution to the pathophysiology of various human diseases, these proteins are targets of many drugs, from antiepileptics to analgesics. Therefore, ion channel dysfunction at the onset of several human ailments are known as channelopathies, which include autoimmune, metabolic, neural, and cardiovascular diseases. The responsible abnormal behavior can be triggered by an altered function, impaired cell biology, genetic alterations, or drug-acquired response, among other events.

This Special Issue will assemble a series of reviews and research articles updating the state of knowledge on membrane channels in health and diseases. These contributions will inform of new progresses in the field and provide new therapeutic approaches for ion-channel-related diseases. This Special Issue is the third and renovated edition of the first Special Issue, “Membrane Channels in Human Diseases” launched in 2018, which has been successful in terms of global visibility and acceptance.

Prof. Dr. Antonio Ferrer-Montiel
Prof. Dr. Antonio Felipe
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

ion channels
nerve transmission
cardiac action potential
non excitable cell physiology
cancer and apoptosis
structure
channelopathies
drug discovery
molecular physiology
molecular architecture
genetics
bacterial physiology and infection
virus infection
plants physiology
toxins

Published Papers (9 papers)

Download All Papers

Research

Jump to: Review

25 pages, 5074 KiB

Open AccessArticle

Clinically Relevant KCNQ1 Variants Causing KCNQ1-KCNE2 Gain-of-Function Affect the Ca²⁺ Sensitivity of the Channel

by Christiane K. Bauer, Tess Holling, Denise Horn, Mário Nôro Laço, Ebtesam Abdalla, Omneya Magdy Omar, Malik Alawi and Kerstin Kutsche

Int. J. Mol. Sci. 2022, 23(17), 9690; https://doi.org/10.3390/ijms23179690 - 26 Aug 2022

Viewed by 1614

Abstract

Dominant KCNQ1 variants are well-known for underlying cardiac arrhythmia syndromes. The two heterozygous KCNQ1 missense variants, R116L and P369L, cause an allelic disorder characterized by pituitary hormone deficiency and maternally inherited gingival fibromatosis. Increased K⁺ conductance upon co-expression of KCNQ1 mutant channels with the beta subunit KCNE2 is suggested to underlie the phenotype; however, the reason for KCNQ1-KCNE2 (Q1E2) channel gain-of-function is unknown. We aimed to discover the genetic defect in a single individual and three family members with gingival overgrowth and identified the KCNQ1 variants P369L and V185M, respectively. Patch-clamp experiments demonstrated increased constitutive K⁺ conductance of V185M-Q1E2 channels, confirming the pathogenicity of the novel variant. To gain insight into the pathomechanism, we examined all three disease-causing KCNQ1 mutants. Manipulation of the intracellular Ca²⁺ concentration prior to and during whole-cell recordings identified an impaired Ca²⁺ sensitivity of the mutant KCNQ1 channels. With low Ca²⁺, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. These features were absent in mutant KCNQ1 channels and in wild-type channels co-expressed with calmodulin and exposed to high intracellular Ca²⁺. Moreover, co-expression of calmodulin with wild-type Q1E2 channels and loading the cells with high Ca²⁺ drastically increased Q1E2 current amplitudes, suggesting that KCNE2 normally limits the resting Q1E2 conductance by an increased demand for calcified calmodulin to achieve effective channel opening. Our data link impaired Ca²⁺ sensitivity of the KCNQ1 mutants R116L, V185M and P369L to Q1E2 gain-of-function that is associated with a particular KCNQ1 channelopathy. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

18 pages, 2285 KiB

Open AccessArticle

Modulation of K_V4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2

by Angela de Benito-Bueno, Paula G. Socuellamos, Yaiza G. Merinero, Pilar Cercos, Carolina Izquierdo, Miguel Daniel-Mozo, Irene Marín-Olivero, Angel Perez-Lara, Juan A. Gonzalez-Vera, Angel Orte, Armando Albert, Mercedes Martin-Martinez, Marta Gutierrez-Rodriguez and Carmen Valenzuela

Int. J. Mol. Sci. 2022, 23(16), 9170; https://doi.org/10.3390/ijms23169170 - 15 Aug 2022

Cited by 2 | Viewed by 1659

Abstract

The transient outward potassium current (I_tof) is generated by the activation of K_V4 channels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by K_V4.3/KChIP2, K_V4.3/KChIP2/DPP6 and K_V4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (K_V4.3/KChIP2, K_V4.3/KChIP2/DPP6 or K_V4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of K_V4.3/KChIP2, K_V4.3/KChIP2/DPP6 and K_V4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in K_V4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the application of trains of pulses to cells expressing K_V4.3/KChIP2 and K_V4.3/KChIP2/KCNE2, but not in K_V4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of K_V4.3/KChIP2 channels to IQM-266. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

13 pages, 2106 KiB

Open AccessArticle

α3β4 Acetylcholine Nicotinic Receptors Are Components of the Secretory Machinery Clusters in Chromaffin Cells

by José Villanueva, Manuel Criado, Yolanda Giménez-Molina, Virginia González-Vélez, Amparo Gil and Luis Miguel Gutiérrez

Int. J. Mol. Sci. 2022, 23(16), 9101; https://doi.org/10.3390/ijms23169101 - 14 Aug 2022

Cited by 1 | Viewed by 1138

Abstract

The heteromeric assembly of α3 and β4 subunits of acetylcholine nicotinic receptors (nAChRs) seems to mediate the secretory response in bovine chromaffin cells. However, there is no information about the localization of these nAChRs in relationship with the secretory active zones in this cellular model. The present work presents the first evidence that, in fact, a population of these receptors is associated through the F-actin cytoskeleton with exocytotic machinery components, as detected by SNAP-25 labeling. Furthermore, we also prove that, upon stimulation, the probability to find α3β4 nAChRs very close to exocytotic events increases with randomized distributions, thus substantiating the clear dynamic behavior of these receptors during the secretory process. Modeling on secretory dynamics and secretory component distributions supports the idea that α3β4 nAChR cluster mobility could help with improving the efficiency of the secretory response of chromaffin cells. Our study is limited by the use of conventional confocal microscopy; in this sense, a strengthening to our conclusions could come from the use of super-resolution microscopy techniques in the near future. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Graphical abstract

14 pages, 4296 KiB

Open AccessArticle

Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart

by Layse Malagueta-Vieira, Julieta Fernández-Ruocco, María P. Hortigón-Vinagre, Víctor Zamora, Julián Zayas-Arrabal, Leyre Echeazarra, Godfrey L. Smith, Martín Vila Petroff, Emiliano Medei, Óscar Casis and Mónica Gallego

Int. J. Mol. Sci. 2022, 23(11), 6021; https://doi.org/10.3390/ijms23116021 - 27 May 2022

Cited by 1 | Viewed by 4051

Abstract

Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (I_to). In vitro, incubation with metformin for 24 h also reduced I_to, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced I_hERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of I_to and I_hERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

24 pages, 4133 KiB

Open AccessArticle

TRPV2: A Key Player in Myelination Disorders of the Central Nervous System

by Jennifer Enrich-Bengoa, Gemma Manich, Tony Valente, Paula Sanchez-Molina, Beatriz Almolda, Carme Solà, Josep Saura, Berta González, Bernardo Castellano and Alex Perálvarez-Marín

Int. J. Mol. Sci. 2022, 23(7), 3617; https://doi.org/10.3390/ijms23073617 - 25 Mar 2022

Cited by 5 | Viewed by 2588

Abstract

Transient potential receptor vanilloid 2 (TRPV2) is widely expressed through the nervous system and specifically found in neuronal subpopulations and some glial cells. TRPV2 is known to be sensitized by methionine oxidation, which results from inflammation. Here we aim to characterize the expression and regulation of TRPV2 in myelination pathologies, such as hypomyelination and demyelination. We validated the interaction between TRPV2 and its putative interactor Opalin, an oligodendrocyte marker, in mixed glial cultures under pro- and anti-inflammatory conditions. Then, we characterized TRPV2 time-course expression in experimental animal models of hypomyelination (jimpy mice) and de-/remyelination (cuprizone intoxication and experimental autoimmune encephalomyelitis (EAE)). TRPV2 showed upregulation associated with remyelination, inflammation in cuprizone and EAE models, and downregulation in hypomyelinated jimpy mice. TRPV2 expression was altered in human samples of multiple sclerosis (MS) patients. Additionally, we analyzed the expression of methionine sulfoxide reductase A (MSRA), an enzyme that reduces oxidated methionines in TRPV2, which we found increased in inflammatory conditions. These results suggest that TRPV2 may be a key player in myelination in accordance with the recapitulation hypothesis, and that it may become an interesting clinical target in the treatment of demyelination disorders. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

16 pages, 4024 KiB

Open AccessArticle

The Expression and Localisation of G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels Is Differentially Altered in the Hippocampus of Two Mouse Models of Alzheimer’s Disease

by Rocío Alfaro-Ruiz, Alejandro Martín-Belmonte, Carolina Aguado, Félix Hernández, Ana Esther Moreno-Martínez, Jesús Ávila and Rafael Luján

Int. J. Mol. Sci. 2021, 22(20), 11106; https://doi.org/10.3390/ijms222011106 - 14 Oct 2021

Cited by 12 | Viewed by 2365

Abstract

G protein-gated inwardly rectifying K⁺ (GIRK) channels are the main targets controlling excitability and synaptic plasticity on hippocampal neurons. Consequently, dysfunction of GIRK-mediated signalling has been implicated in the pathophysiology of Alzheimer´s disease (AD). Here, we provide a quantitative description on the expression and localisation patterns of GIRK2 in two transgenic mice models of AD (P301S and APP/PS1 mice), combining histoblots and immunoelectron microscopic approaches. The histoblot technique revealed differences in the expression of GIRK2 in the two transgenic mice models. The expression of GIRK2 was significantly reduced in the hippocampus of P301S mice in a laminar-specific manner at 10 months of age but was unaltered in APP/PS1 mice at 12 months compared to age-matched wild type mice. Ultrastructural approaches using the pre-embedding immunogold technique, demonstrated that the subcellular localisation of GIRK2 was significantly reduced along the neuronal surface of CA1 pyramidal cells, but increased in its frequency at cytoplasmic sites, in both P301S and APP/PS1 mice. We also found a decrease in plasma membrane GIRK2 channels in axon terminals contacting dendritic spines of CA1 pyramidal cells in P301S and APP/PS1 mice. These data demonstrate for the first time a redistribution of GIRK channels from the plasma membrane to intracellular sites in different compartments of CA1 pyramidal cells. Altogether, the pre- and post-synaptic reduction of GIRK2 channels suggest that GIRK-mediated alteration of the excitability in pyramidal cells could contribute to the cognitive dysfunctions as described in the two AD animal models. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

11 pages, 1890 KiB

Open AccessArticle

Anti-Inflammatory Effect of Licochalcone A via Regulation of ORAI1 and K⁺ Channels in T-Lymphocytes

by Hong T. L. Phan, Hyun J. Kim, Sungwoo Jo, Woo K. Kim, Wan Namkung and Joo H. Nam

Int. J. Mol. Sci. 2021, 22(19), 10847; https://doi.org/10.3390/ijms221910847 - 07 Oct 2021

Cited by 10 | Viewed by 2299

Abstract

Calcium signaling plays a vital role in the regulation of various cellular processes, including activation, proliferation, and differentiation of T-lymphocytes, which is mediated by ORAI1 and potassium (K⁺) channels. These channels have also been identified as highly attractive therapeutic targets for immune-related diseases. Licochalcone A is a licorice-derived chalconoid known for its multifaceted beneficial effects in pharmacological treatments, including its anti-inflammatory, anti-asthmatic, antioxidant, antimicrobial, and antitumorigenic properties. However, its anti-inflammatory effects involving ion channels in lymphocytes remain unclear. Thus, the present study aimed to investigate whether licochalcone A inhibits ORAI1 and K⁺ channels in T-lymphocytes. Our results indicated that licochalcone A suppressed all three channels (ORAI1, Kv1.3, and KCa3.1) in a concentration-dependent matter, with IC₅₀ values of 2.97 ± 1.217 µM, 0.83 ± 1.222 µM, and 11.21 ± 1.07 µM, respectively. Of note, licochalcone A exerted its suppressive effects on the IL-2 secretion and proliferation in CD3 and CD28 antibody-induced T-cells. These results indicate that the use of licochalcone A may provide an effective treatment strategy for inflammation-related immune diseases. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Graphical abstract

Review

Jump to: Research

18 pages, 1226 KiB

Open AccessReview

Palmitoylation of Voltage-Gated Ion Channels

by Silvia Cassinelli, Carla Viñola-Renart, Anna Benavente-Garcia, María Navarro-Pérez, Jesusa Capera and Antonio Felipe

Int. J. Mol. Sci. 2022, 23(16), 9357; https://doi.org/10.3390/ijms23169357 - 19 Aug 2022

Cited by 10 | Viewed by 2527

Abstract

Protein lipidation is one of the most common forms of posttranslational modification. This alteration couples different lipids, such as fatty acids, phospho- and glycolipids and sterols, to cellular proteins. Lipidation regulates different aspects of the protein’s physiology, including structure, stability and affinity for cellular membranes and protein–protein interactions. In this scenario, palmitoylation is the addition of long saturated fatty acid chains to amino acid residues of the proteins. The enzymes responsible for this modification are acyltransferases and thioesterases, which control the protein’s behavior by performing a series of acylation and deacylation cycles. These enzymes target a broad repertoire of substrates, including ion channels. Thus, protein palmitoylation exhibits a pleiotropic role by differential modulation of the trafficking, spatial organization and electrophysiological properties of ion channels. Considering voltage-gated ion channels (VGICs), dysregulation of lipidation of both the channels and the associated ancillary subunits correlates with the development of various diseases, such as cancer or mental disorders. Therefore, a major role for protein palmitoylation is currently emerging, affecting not only the dynamism and differential regulation of a moiety of cellular proteins but also linking to human health. Therefore, palmitoylation of VGIC, as well as related enzymes, constitutes a novel pharmacological tool for drug development to target related pathologies. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

49 pages, 4308 KiB

Open AccessReview

Signaling Mechanisms and Pharmacological Modulators Governing Diverse Aquaporin Functions in Human Health and Disease

by Kim Wagner, Lucas Unger, Mootaz M. Salman, Philip Kitchen, Roslyn M. Bill and Andrea J. Yool

Int. J. Mol. Sci. 2022, 23(3), 1388; https://doi.org/10.3390/ijms23031388 - 26 Jan 2022

Cited by 48 | Viewed by 8947

Abstract

The aquaporins (AQPs) are a family of small integral membrane proteins that facilitate the bidirectional transport of water across biological membranes in response to osmotic pressure gradients as well as enable the transmembrane diffusion of small neutral solutes (such as urea, glycerol, and hydrogen peroxide) and ions. AQPs are expressed throughout the human body. Here, we review their key roles in fluid homeostasis, glandular secretions, signal transduction and sensation, barrier function, immunity and inflammation, cell migration, and angiogenesis. Evidence from a wide variety of studies now supports a view of the functions of AQPs being much more complex than simply mediating the passive flow of water across biological membranes. The discovery and development of small-molecule AQP inhibitors for research use and therapeutic development will lead to new insights into the basic biology of and novel treatments for the wide range of AQP-associated disorders. Full article

(This article belongs to the Special Issue Membrane Channels in Physiology and Pathology)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Membrane Channels in Physiology and Pathology

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI